Cyclization-activated prodrugs. Basic carbamates of 4-hydroxyanisole.
A series of basic carbamates of 4-hydroxyanisole was prepared and evaluated as progenitors of this melanocytotoxic phenol. All of the carbamates were relatively stable at low pH but released 4-hydroxyanisole cleanly at pH 7.4 at rates that were structure dependent. A detailed study of the N-methyl-N-[2-(methylamino)ethyl]carbamate showed that generation of the parent phenol followed first-order kinetics with t1/2 = 36.3 min at pH 7.4, 37 degrees C, and was accompanied by formation of N,N'-dimethylimidazolidinone. These basic carbamates are examples of cyclization-activated prodrugs in which generation of the active drug is not linked to enzymatic cleavage but rather depends solely upon a predictable, intramolecular cyclization-elimination reaction.
Saari
W S
WS
Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Schwering
J E
JE
Lyle
P A
PA
Smith
S J
SJ
Engelhardt
E L
EL
D000818:Animals; D000840:Anisoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D003500:Cyclization; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008544:Melanocytes / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D011355:Prodrugs
D000840:Anisoles; D002219:Carbamates; D011355:Prodrugs; C009760:mequinol